Premium
EGF cooperates with TGFβ to regulate PAI‐1 expression by a synergistic increase in transcription and stabilization of mRNA
Author(s) -
Song Xiaoling,
NilsenHamilton Marit
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb71
Subject(s) - mapk/erk pathway , transforming growth factor , microbiology and biotechnology , smad , kinase , biology , p38 mitogen activated protein kinases , chemistry , plasminogen activator inhibitor 1 , signal transduction , amphiregulin , epidermal growth factor , plasminogen activator , cancer research , endocrinology , receptor , biochemistry
PAI‐1, the primary inhibitor of plasminogen‐activators, plays an important role in extracellular matrix remodeling and fibrinolysis. Over‐expression of PAI‐1 is found in many diseases including cancer, fibrosis and metabolic syndrome. EGF and TGFβ synergistically elevate PAI‐1 expression up to 80‐fold in mink lung epithelial cell (Mv1Lu) and human hepatoma (HepG2) cells. The mechanism of synergism was investigated in Mv1Lu cells in which it was found that, while EGF and TGFβ synergistically increase PAI‐1 mRNA transcription, EGF alone increases PAI‐1 mRNA stability. TGFβ also increases the sensitivity of the cellular response to EGF. The results of experiments using specific chemical inhibitors of protein kinases, including MEK1/2, p38 MAPK, PI3K, SRC and JNK, showed that synergism between EGF and TGFβ was lost only when ERK1/2 phosphorylation was blocked. Growth factors other than EGF that activate the MAPK pathway, including IGF‐1, FGF‐2 and TNFα, also synergize with TGFβ to increase PAI‐1 expression. Investigation of the responses to EGF and TGFβ of several recombinant promoters containing different combinations of transcription elements identified an interaction between AP‐1 and a SMAD as the probable mechanism of synergism. A model to explain the synergism is proposed in which Fos is uniquely activated in response to the combination of EGF and TGFβ but not in response to either growth factor alone.